Process for the production of oxandrolone

ABSTRACT

The present invention relates to a process for the synthesis of oxandrolone from mestanolone. The process comprises the steps of: (a) oxidizing mestanolone to form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) hydroxylating the 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one to form 1α,2α,17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the 1α,2α,17β-trihydroxy-17α-methylandrostan-3-one to form 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid; and (d) reducing the 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid to form oxandrolone.

FIELD OF THE INVENTION

[0001] The present invention relates to a process for the synthesis ofoxandrolone. The present invention further relates to a process whichprovides oxandrolone in relatively high yields and purity.

BACKGROUND OF THE INVENTION

[0002] Oxandrolone (i.e.,17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one) is a known anabolicsteroid that has various therapeutic uses. Methods of producingoxandrolone are known. For example, U.S. Pat. No. 3,109,016 discloses aprocess of manufacture of 17-oxygenated 2-oxa-5α-androstan-3-ones. The'016 patent discloses the reaction of17β-hydroxy-17α-methyl-5α-androst-1-en-3-one in methylene chloride andmethanol with ozone to produce methyl17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oate and,alternatively, with ozone in methylene chloride to yield17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic formicanhydride. According to the '016 patent, the 1,2-seco intermediates areconverted to the corresponding anabolic 2-oxa compound by treatment witha reducing agent in aqueous medium. The methyl17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oate may becontacted with sodium borohydride in aqueous sodium hydroxide to form17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one (i.e., oxandrolone).

[0003] U.S. Pat. No. 3,128,283, which relates to 17-oxygenatedandrostane and estrane derivatives in which the A ring contains alactone structure, also discloses an example of the production ofoxandrolone. 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one is reacted inaqueous acetic acid with osmium tetroxide and lead tetracetate to afford17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid.This compound is converted to17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one by reduction with sodiumborohydride in aqueous sodium hydroxide. A disadvantage of methods thatuse lead tetracetate, however, is that lead tetracetate is a highlytoxic compound.

[0004] 17-hydroxy-17-methyl-5-androst-1-en-3-one may be formed from17-hydroxy-17-methyl-5-androstan-3-one. For example, U.S. Pat. No.2,260,328 discloses mixing 17-hydroxy-17-methyl-5-androstan-3-one inglacial acetic acid solution with bromine. This product is precipitatedand purified. The product is then heated with dimethylaniline orpotassium acetate in glacial acetic acid under pressure to eliminatehydrogen bromide, thus forming17-hydroxy-17-methyl-5-androst-1-en-3-one.

[0005] Methods using bromination-dehydrobromination are disadvantageousdue to low yields. For example, these methods typically generate thecompound in a 15-30% overall yield with the compound being contaminatedin approximately 5-10% of methyl testosterone. Such methods generallyrequire the use of chromatography such as silica gel chromatography toobtain pure product.

[0006] It would be advantageous to provide a process for producingoxandrolone that results in the formation of oxandrolone in relativelyhigh yields and purity.

SUMMARY OF THE INVENTION

[0007] The present invention relates to a process for the synthesis ofoxandrolone from mestanolone. In one aspect of the present invention, aprocess is provided comprising the steps of: (a) oxidizing mestanoloneto form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) hydroxylatingthe 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one to form1α,2α,17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the1α,2α,17β-trihydroxy-17α-methylandrostan-3-one to form17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid;and (d) reducing the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid toform oxandrolone.

[0008] In another aspect of the present invention, a process is providedfor the production of oxandrolone comprising the steps of: (a) oxidizingmestanolone using o-iodoxybenzoic acid (IBX) to form17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) hydroxylating the17β-hydroxy-17α-methyl-5α-androst-1-en-3-one to form1α,2α,17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the1α,2α,17β-trihydroxy-17α-methylandrostan-3-one to form17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid;and (d) reducing the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid toform oxandrolone. At least two by-products are formed in step (a) thatare non-reactive to steps (b) and (c).

[0009] In a further aspect of the present invention, mestanolone isoxidized using IBX to form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one.The 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one is hydroxylated usingosmium tetroxide to form 1α,2α,17β-trihydroxy-17α-methylandrostan-3-one.The 1α,2α,17β-trihydroxy-17α-methylandrostan-3-one is cleaved usingsodium metaperiodate to form17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid.The 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acidis then reduced using sodium borohydride followed by an acid treatmentto form oxandrolone.

[0010] In yet another aspect of the present invention, mestanolone isreacted with IBX to form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one.The 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one is reacted with osmiumtetroxide and N-methylmorpholine N-oxide to form1α,2α,17β-trihydroxy-17α-methylandrostan-3-one. The1α,2α,17β-trihydroxy-17α-methylandrostan-3-one is reacted with sodiummetaperiodate to form17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid.Oxandrolone is then formed from the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid byreacting the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acidwith sodium borohydride followed by an acid treatment comprisingaddition of hydrochloric acid.

BRIEF DESCRIPTION OF THE DRAWING

[0011] The FIGURE illustrates the general synthetic scheme of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

[0012] According to the present invention, oxandrolone is produced usingmestanolone (i.e., 17β-hydroxy-17α-methyl-5α-androstan-3-one) as astarting material. The mestanolone is oxidized in order to form an enoneintermediate (i.e., 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one). Theenone is hydroxylated to form an intermediate triol (i.e.,1α,2α,17β-trihydroxy-17α-methylandrostan-3-one), which is cleaved toform an intermediate acid (i.e.,17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid).The acid is reduced to form oxandrolone.

[0013] The mestanolone is preferably oxidized using IBX (o-iodoxybenzoicacid), and the enone is preferably hydroxylated using osmium tetroxide.In one preferred aspect, a catalytic amount of osmium tetroxide is usedalong with N-methylmorpholine N-oxide. The triol is preferably cleavedusing sodium metaperiodate, and the acid is preferably reduced usingsodium borohydride followed by an acid treatment (i.e., addition of anacid or acids). In one preferred embodiment, the acid treatmentcomprises addition of hydrochloric acid.

[0014] Unless otherwise stated, the following terms used in thespecification and claims have the meanings given below:

[0015] “Oxidize” or “oxidizing” means to undergo or cause to undergo achemical reaction resulting in a loss of electrons or hydrogen, or again of oxygen.

[0016] “Hydroxylate” or “hydroxylating” means to undergo or cause toundergo a chemical reaction resulting in an addition of one or morehydroxyl groups.

[0017] “Cleave” or “cleaving” means to undergo or cause to undergo achemical reaction resulting in loss of a covalent bond between twoatoms.

[0018] “Reduce” or “reducing” means to undergo or cause to undergo achemical reaction resulting in a gain of electrons or hydrogen, or aloss of oxygen.

[0019] The present invention provides a method for forming oxandrolonein high overall yields (e.g., 30-40%) and high purity (e.g., greaterthan 98%). This method provides advantages over other known methods forproducing oxandrolone as well as other methods of performing thesynthesis steps disclosed herein. For example, by using IBX as theoxidizing agent in the first step, the enone intermediate is produced inthe present invention in high yields (e.g., about 70%). Although the useof IBX results in the production of one or more by-products (typicallyat least two by-products), the by-products are non-reactive to thesubsequent hydroxylation and cleavage steps of the process, resulting inquantitative yields of the desired products. The nonreactive by-productsdo not affect the recovery of oxandrolone as (1) the oxandrolone may beeasily removed or separated (e.g., by crystallization of the finalproduct) after the reduction step of the process or (2) the by-productsmay be easily removed or separated after the reduction step of theprocess. Thus, the present invention advantageously provides anefficient process for the production of oxandrolone that results indecreased production time, decreased production cost, and increasedoverall yield as compared to known methods. The present inventionenables the production of oxandrolone without the need forchromatography, such as silica gel column chromatography, at any step ofthe process. Thus, the desired product may be obtained through the stepsof the present invention in sufficiently pure form as to substantiallyeliminate purification procedures normally required, e.g.,chromatography. A preferred embodiment of the process of the presentinvention also avoids the use of (or is performed in the substantialabsence of) lead tetraacetate, a highly toxic compound used in knownmethods for oxidative cleavage.

[0020] The general synthetic scheme of the present invention is shown inthe FIGURE. The steps of the general method are: step (a), oxidation ofmestanolone to form an enone; step (b), hydroxylation of the enone toform a triol; step (c), cleavage of the triol to form an acid; and step(d), reduction of the acid to form oxandrolone.

[0021] Step (a) is as follows:

[0022] In this step, mestanolone (I) is reacted with an oxidizing agentor agents in a suitable solvent or solvent mixture at elevatedtemperature to produce the enone (II) (i.e.,17β-hydroxy-17α-methyl-5α-androst-1-en-3-one). The oxidizing agent ispreferably IBX, although other oxidizing agents such as, for example,bis(acetoxy)iodobenzene, and iodosobenzene may also be used. The molarratio of mestanolone to oxidizing agent is typically from about 1:1 toabout 1:2, preferably about 1:1.5. When IBX is used as the oxidizingagent, the molar ratio of mestanolone to IBX is preferably about 1:1.5.Suitable solvents or solvent mixtures include fluorobenzene or toluenewith dimethyl sulfoxide (DMSO). Preferably, the solvent mixture will betoluene and DMSO. The volume ratio of toluene to DMSO typically will beabout 1:1 to about 3:1, preferably about 2:1. The reaction is performedat an elevated temperature, typically in a temperature range from about55° C. to about 85° C., preferably in a temperature range from about 60°C. to about 75° C., and more preferably in a temperature range fromabout 65° C. to about 70° C. The reactants generally are heated forabout 6 to about 48 hours. The product yield of this reaction and thepurity of the reaction product will depend upon the oxidizing agent andthe reaction temperature. When IBX is used as the oxidizing agent, theyield is typically about 65% to about 75% in a temperature range ofabout 68° C. to about 72° C. As mentioned above, when IBX is used as theoxidizing agent, two by-products are typically produced, but,advantageously, are nonreactive to the subsequent hydroxylation andcleavage steps (i.e., steps (b) and (c)).

[0023] IBX (o-iodoxybenzoic acid) is a cheap, nontoxic reagent. It maybe produced from any known method. Preferably, the IBX will be preparedas illustrated in the synthesis scheme shown below:

[0024] According to the reaction scheme, 2-iodobenzoic acid is reactedwith Oxone® brand monopersulfate compound (available from DuPont®) inwater at about 75° C. to about 80° C. to form IBX.

[0025] Step (b) is as follows:

[0026] In step (b), the enone (II) produced in step (a) (i.e.,17β-hydroxy-17α-methyl-5α-androst-1-en-3-one) is reacted with astereospecific hydroxylating agent or agents in a suitable solvent orsolvent mixture to produce the intermediate triol (III) (i.e.,1α,2α,17β-trihydroxy-17α-methylandrostan-3-one). The hydroxylating agentis preferably osmium tetroxide, although other hydroxylating agents suchas, for example, potassium permanganate, may be used. In one preferredembodiment, osmium tetroxide is used in a catalytic amount along withN-methylmorpholine N-oxide (e.g., a 50% aqueous solution thereof).Osmium tetroxide may also be used alone or in a catalytic amount incombination with t-butyl hydroperoxide, barium chlorate, or anothersuitable oxidant or oxidants. The molar ratio of enone to hydroxylatingagent is typically from about 1:0.001 to about 1:0.01, preferably about1:0.005. Suitable solvents or solvent mixtures include tetrahydrofuran,dioxane, acetone, t-butyl alcohol, water, and mixtures thereof.Preferably, the solvent mixture will be tetrahydrofuran (THF) andacetone. The volume ratio of THF to acetone typically will be about 1:3to about 3:1, preferably about 1:1. The reaction generally is performedat room temperature, typically in a temperature range from about 10° C.to about 50° C., preferably in a temperature range from about 20° C. toabout 30° C. The reactants are typically allowed to react for about 6 toabout 24 hours. The product yield of this reaction and the purity of thereaction product will depend upon the hydroxylating agent and thereaction temperature. When osmium tetroxide is used in a catalyticamount along with N-methylmorpholine N-oxide as a cooxidant, the yieldis typically about 75% to about 95% in a temperature range of about 20°C. to about 30° C.

[0027] Step (c) is as follows:

[0028] In this step, the triol (III) produced in step (b) (i.e.,1α,2α,17β-trihydroxy-17α-methylandrostan-3-one) is reacted with anoxidative cleaving agent or agents in a suitable solvent or solventmixture to produce the intermediate acid (IV) (i.e.,17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid).The cleaving agent is typically sodium metaperiodate, although othercleaving agents may be used such as, for example, lead tetraacetate andozone. The molar ratio of triol to cleaving agent is typically about 1:3to about 1:1, preferably about 1:2. Suitable solvents or solventmixtures include tetrahydrofuran, dichloromethane, dioxane, water,tert-butyl alcohol, and mixtures thereof. Preferably, the solventmixture will be THF and dichloromethane. The volume ratio of THF todichloromethane typically will be about 1:1 to about 1:5, preferablyabout 1:4. The reaction is performed at room temperature, typically in atemperature range from about 20° C. to about 40° C., preferably in atemperature range from about 25° C. to about 35° C. The reactants aretypically allowed to react for about 6 to about 24 hours. The productyield of this reaction and the purity of the reaction product willdepend upon the cleaving agent and the reaction temperature. When sodiummetaperiodate is used as the cleaving agent, the yield is typicallyabout 75% to about 95% in a temperature range of about 25° C. to about30° C.

[0029] Step (d) is as follows:

[0030] In this step, the acid (IV) produced in step (c) (i.e.,17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid) isreacted with a reducing agent or agents in a suitable solvent or solventmixture followed by an acid treatment (i.e., the addition of an acid oracids) to produce oxandrolone (V). The reducing agent is typicallysodium borohydride, although other reducing agents such as, for example,lithium tri-tert-butoxyaluminum hydride, may also be used. The molarratio of intermediate acid (IV) to reducing agent is typically about 1:1to about 1:2, preferably about 1:1.5. When sodium borohydride is used asthe reducing agent, the molar ratio of the intermediate acid (IV) tosodium borohydride is preferably about 1:1.5. The acid treatmentcomprises addition of a suitable acid or acids such as, for example, anorganic and/or an inorganic acid, and preferably comprises addition of amineral acid such as, for example, hydrochloric acid. In one embodiment,sodium borohydride is used as the reducing agent and hydrochloric acidis added as the acid treatment. The solution is typically acidified bythe acid treatment to a pH range from about 1 to about 4, preferablyfrom about 2 to about 3. Suitable solvents or solvent mixtures includetetrahydrofuran, dimethylformamide, dioxane, and mixtures thereof.Preferably, the solvent is dimethylformamide. The reaction is performedat low temperature, typically in a temperature range from about 0° C. toabout 25° C., preferably in a temperature range from about 10° C. toabout 20° C. The reactants are typically allowed to react for about 6 toabout 24 hours. The product yield of this reaction and the purity of thereaction product will depend upon the reducing agent and the reactiontemperature. When sodium borohydride is used as the reducing agentfollowed by an acid treatment comprising addition of hydrochloric acid,the temperature range will be about 0° C. to about 20° C. The overallyield for the entire process is typically about 30% to about 40%.

[0031] As discussed above, when IBX is used as the oxidizing agent instep (a) of the process, two by-products are typically produced. Thesetwo by-products do not react in steps (b) and (c), but are believed toreact in step (d), although the by-products do not affect the isolationof the final product. The final product may be isolated from theby-products by techniques such as crystallization of the oxandrolone,which typically results in a product that is greater than 98% pure.Alternatively, the by-products may be separated by techniques such ascrystallization. In addition, isolation of the final product does notrequire time-consuming procedures such as chromatography.

EXAMPLES

[0032] The invention will be further explained by the followingillustrative examples that are intended to be non-limiting.

Example 1 Synthesis of 17α-methyl-17β-hydroxy-5α-androst-1-en-3-one

[0033] A mixture of mestanolone (55.3 g, 0.182 mol) and IBX (76.5 g,0.273 mol, 1.5 eq.) in 1800 ml toluene:DMSO (2:1) was heated at 65-70°C. for 48 h after which time the beginning clear solution turned into asuspension. TLC (thin layer chromatography) indicated the disappearanceof starting mestanolone and the appearance of the desired product andtwo by-products. After cooling to RT (room temperature), the reactionmixture was filtered on a frit and solid washed with ethyl acetate(2×200 ml). The filtrate was diluted with 1000 ml of ethyl acetate andthe resulting organic phase was washed with 1000 ml each of 5% NaHCO₃,water, and brine. After drying over sodium sulfate, removal of thesolvents on a rotavapor gave 56.0 g of a crude products mixturecontaining the required product (i.e.,17α-methyl-17β-hydroxy-5α-androst-1-en-3-one) along with two minorby-products.

Example 2 Synthesis of 1α,2α,17β-trihydroxy-17α-methylandrostan-3-one

[0034] The crude product mixture obtained in Example 1 above (56.0 g, 20mmol) was dissolved in 600 ml THF and then diluted with 600 ml ofacetone. To this solution was added a 50 wt % aqueous solution ofN-methylmorpholine N-oxide (65.4 g, 280 mmol) followed by a 1% aqueoussolution of OSO₄ (24 ml, 0.94 mmol) and 28 ml of water. The reactionmixture was stirred at RT overnight (˜18 hr). TLC showed the completedisappearance of the enone and the appearance of a polar product; theby-products from Example 1 remained unaffected. 2.0 g of potassiumcarbonate was added to the mixture and stirred for 30 minutes, and thevolatiles were removed on a rotavapor at RT. The reaction mixture wastaken up in 2000 ml each of ethyl acetate and water and was then shakenvigorously in a sep-funnel. After removing the aqueous phase, theorganic phase was washed with 1000 ml each of water, 5% aqueous solutionof sodium metabisulphite, water, and brine. Afer drying over sodiumsulfate, removal of solvents on rotavapor yielded 61.6 g of a crudeproducts mixture.

Example 3 Synthesis of17β-hydroxy-17α-methyl-1-oxo-1,2-seco-A-nor-5α-androstan-2-oic Acid

[0035] The crude product mixture obtained from Example 2 above (61.6 g,185.0 mmol) was dissolved in 350 ml THF and then the resulting solutionwas diluted with 1400 ml of dichloromethane. Powdered sodiummetaperiodate (87.5 g, 409.0 mmol, 2.2 eq.) was added in one lot to thestirring mixture followed by 50 ml of water. The resulting mixture wasvigorously stirred for 24 hr after which time all of the startingmaterial disappeared as indicated by TLC. Anhydrous sodium sulfate wasadded to the reaction mixture and allowed to stir for 10 minutes. Thesolids were filtered off on a frit and washed with dichloromethane(2×360 ml). Removal of the solvents from the filtrate yielded 60.2 g ofwhite solid.

Example 4 Synthesis of 17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one

[0036] The white product obtained in Example 3 above (60.2 g, 186.6mmol) was dissolved in 250.0 mL DMF (dimethyl formamide). The DMF (250.0mL) solution of crude acid (60.2 g, 186.6 mmol) was added drop wise to astirring suspension of sodium borohydride (10.7 g, 189.4 mmol, 1.5 eq.)in 160.0 ml of DMF at 0-5° C. The reaction mixture was stirred for 24 hrat RT and then cooled back to 0-5° C. 1 N NaOH (103.0 ml) aqueoussolution was then added drop wise to the stirring solution whilemaintaining the temperature below 10° C. The reaction mixture wasdiluted with 740.0 ml of water, transferred to a sep-funnel, andextracted with 2×600 ml of dichloromethane followed by 300 ml of ether.The aqueous layer was transferred back to a flask containing a stirrer.1200 ml of a 1:1 mixture of THF and ethyl acetate was added to theaqueous layer and then acidified by drop wise addition of a 3N aqueoushydrochloric acid solution (˜160 ml was needed to get pH of 2-3) whilekeeping the temperature around 10° C. The resulting mixture was pouredinto a sep-funnel containing 600 ml of ethyl acetate. The organic phasewas separated and then successively washed with water (2×500 ml) andbrine. After drying over sodium sulfate, the solution was partiallyconcentrated on a rotavapor yielding white crystalline solid, which wascollected on a frit and washed with ether to give 18.6 g (33% overallyield) of oxandrolone.

[0037] While the invention has been described in detail and withreference to specific embodiments thereof, it will be apparent to oneskilled in the art that various changes and modifications can be madewithout departing from the spirit and scope of the invention.

What is claimed is:
 1. A process for the production of oxandrolonecomprising the steps of: (a) oxidizing mestanolone using IBX to form17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) hydroxylating the17β-hydroxy-17α-methyl-5α-androst-1-en-3-one using osmium tetroxide toform 1α,2α,17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the1α,2α,17β-trihydroxy-17α-methylandrostan-3-one using sodiummetaperiodate to form17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid;and (d) reducing the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acidusing sodium borohydride followed by an acid treatment to formoxandrolone.
 2. The process of claim 1 wherein at least two by-productsare formed in step (a) that are non-reactive to steps (b) and (c). 3.The process of claim 1 wherein step (b) is carried out using osmiumtetroxide and N-methylmorpholine N-oxide.
 4. The process of claim 1wherein the acid treatment of step (d) comprises addition ofhydrochloric acid.
 5. The process of claim 1 wherein the process isperformed without the use of lead tetraacetate.
 6. A process for theproduction of oxandrolone comprising the steps of: (a) oxidizingmestanolone to form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b)hydroxylating the 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one to form1α,2α,17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the1α,2α,17β-trihydroxy-17α-methylandrostan-3-one to form17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid;and (d) reducing the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid toform oxandrolone.
 7. The process of claim 6 wherein step (a) is carriedout using IBX.
 8. The process of claim 6 wherein at least twoby-products are formed in step (a) that are non-reactive to steps (b)and (c).
 9. The process of claim 6 wherein step (b) is carried out usingosmium tetroxide.
 10. The process of claim 9 wherein step (b) is carriedout using osmium tetroxide and N-methylmorpholine N-oxide.
 11. Theprocess of claim 6 wherein step (c) is carried out using sodiummetaperiodate.
 12. The process of claim 6 wherein step (d) is carriedout using sodium borohydride followed by an acid treatment.
 13. Theprocess of claim 12 wherein the acid treatment comprises addition ofhydrochloric acid.
 14. The process of claim 6 wherein the process isperformed without the use of lead tetraacetate.
 15. A process for theproduction of oxandrolone comprising the steps of: (a) reactingmestanolone with IBX to form17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) reacting the17β-hydroxy-17α-methyl-5α-androst-1-en-3-one with osmium tetroxide andN-methylmorpholine N-oxide to form1α,2α,17β-trihydroxy-17α-methylandrostan-3-one; (c) reacting the1α,2α,17β-trihydroxy-17α-methylandrostan-3-one with sodium metaperiodateto form 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oicacid; (d) forming oxandrolone from the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid byreacting the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acidwith sodium borohydride followed by an acid treatment comprisingaddition of hydrochloric acid.
 16. The process of claim 15 wherein themolar ratio of mestanolone to IBX in step (a) is about 1:1.5.
 17. Theprocess of claim 15 wherein step (a) is performed in a 2:1 mixture oftoluene to dimethyl sulfoxide, step (b) is performed in a 1:1 mixture oftetrahydrofuran to acetone, and step (c) is performed in a 1:4 mixtureof tetrahydrofuran to CH₂Cl₂.
 18. The process of claim 15 wherein theprocess is performed without the use of lead tetraacetate.
 19. Theprocess of claim 15 wherein at least two by-products are formed in step(a) that are non-reactive to steps (b) and (c).
 20. A process for theproduction of oxandrolone comprising the steps of: (a) oxidizingmestanolone using IBX to form17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) hydroxylating the17β-hydroxy-17α-methyl-5α-androst-1-en-3-one to form1α,2α,17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the1α,2α,17β-trihydroxy-17α-methylandrostan-3-one to form17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid;and (d) reducing the17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid toform oxandrolone; wherein at least two by-products are formed in step(a) that are non-reactive to steps (b) and (c).
 21. Oxandrolone obtainedby the process of claim 1.